RESULTS AND DISCUSSION
Systematic review of the literature and formulation of the first recommendation
The initial search in the literature retrieved 219 studies, 33 of which were selected
for full reading. Manual search identified 11 more, resulting in 44 studies ([Figure 1]). After full reading of those studies, only 20 were included in the qualitative
analysis and 15 in the quantitative synthesis. The studies by Finnerup et al. (2002)[14], Jungehulsing et al. (2013)[15], Drewes et al. (1994)[16], and Vestergaard et al. (2001)[17] were excluded from quantitative synthesis because they did not present means and
standard deviations as central and dispersion measures, making it imprecise to include
them in the meta-analysis[18]. The study by Leijon et al. (1989)[19] was also excluded from the quantitative synthesis as, in addition to having presented
mean and standard deviations as central tendency and dispersion measures, the statistical
analysis was performed with non-parametric tests, making these measures inappropriate.
The 20 studies included pharmacological agents employed in the treatment of central
pain in multiple sclerosis[20],[21],[22],[23],[24],[25],[26],[27],[28], spinal cord injury[16],[22],[27],[29],[30], stroke[15],[20]
–
[22],[31], and brachial plexus injury with avulsion[32]. They used as pharmacological agents pregabalin[20],[21],[22],[31], gabapentin[29], duloxetine[26],[27],[30], amitriptyline[19], combinations of cannabidiol/delta-9-tetrahydrocannabinol (CBD/THC)[14],[24],[32],[33], lamotrigine[14],[15],[24], levetiracetam[15], carbamazepine[19], dronabinol[28], and valproate[16].
Figure 1 Flowchart of the literature search in Medline (via Pubmed).
Fifteen studies were excluded for not having a control group[34],[35],[36],[37],[38],[39], for being observational instead of randomized controlled trials (RCT)[38],[40], for including individuals with pain other than CNP[41],[42],[43],[44],[45], for having less than 10 participants in the treatment arm[46], and for using oral and intravenous drugs in association[47].
The quantitative synthesis showed that pharmacological treatment with the above-described
drugs significantly decreased pain intensity (Supplementary Figure S1). However, there
was a great heterogeneity among the studies (I2=93%), making this statement inconsistent. Then, a separate meta-analysis was run
by grouping different drugs in the treatment of CNP. A second general quantitative
synthesis was performed including studies in which all or all-but-one GRADE items
were considered as low-risk of bias (n=8). This second analysis showed an overall
efficacy (large effect size - 0.85[0.49-1.22]) for the use of pharmacological agents
to treat CNP (Supplementary Figure S2), this time with higher homogeneity (I2=24%). This second analysis included six positive studies using pregabalin[21],[22], and duloxetine[30] to treat spinal cord injury (SCI)-CNP, and formulations of CBD/THC[33],[37] and duloxetine[26] to treat multiple sclerosis-related CNP, as well as two studies using lamotrigine[23] and levetiracetam[24], and dronabinol[28] to treat MS-CNP, and one study using pregabalin to treat central poststroke pain
(CPSP)[31].
The classification of studies according to the European Federation of Neurological
Societies (EFNS) criteria was the next step in the definition of the final recommendations
of this guideline ([Table 1]). This table also contains the final recommendations based on the ratings of 12
specialists from the Brazilian Academy of Neurology, who voluntarily responded to
the query to vote in the second round of the study. An agreement above 90% was obtained
for the recommendations. These ratings took into account the results of the quantitative
synthesis, the EFNS level of recommendation, the availability of the drugs in the
Brazilian public health system, their cost, side-effect profile, and historical national
clinical experience with each drug. Drugs were eventually classified as of first-,
second- and third-line according to all these factors.
Table 1
Main results from selected studies.
|
Studies
|
Drug/condition
|
Line of treatment according to the consensus
|
Results (+/-)
|
EFNS Classification
|
Level of Recommendation
|
Adverse effects
|
Availability in SUS / Mean cost per month
|
|
Levendoglu et al 2004
|
Gabapentin/SCI
|
first-line
|
+
|
II
|
C (Possibly effective)
|
++
|
Available (Formulary for high cost medicines) / $$$
|
|
Vranken et al., 2011
|
Duloxetine/CPSP, SCI
|
first-line
|
–
|
II
|
C (Possibly effective)
|
++
|
Not available / $$
|
|
Vollmer et al., 2013
|
Duloxetine/MS
|
+
|
I
|
|
Brown et al., 2015
|
Duloxetine/ MS
|
+
|
II
|
|
Leijon et al., 1989
|
Amitriptyline/CPSP
|
first-line
|
+
|
II
|
C (Possibly effective)
|
+++
|
Available / $
|
|
Siddal et al., 2006
|
Pregabalin/ SCI
|
second-line
|
+
|
II
|
C (Possibly effective)
|
++
|
Not available / $$$
|
|
Cardenas et al., 2013
|
Pregabalin/SCI
|
+
|
I
|
|
|
Vranken et al., 2008
|
Pregabalin/CPSP, SCI
|
+
|
II
|
|
|
Kim et al., 2011
|
Pregabalin/CPSP
|
–
|
I
|
|
|
Vestergaard et al., 2001
|
Lamotrigine/CPSP
|
second-line
|
+
|
II
|
B (Possibly ineffective)
|
++
|
Not available / $$
|
|
Breuer et al., 2007
|
Lamotrigine/MS
|
–
|
II
|
|
Finnerup et al., 2002
|
Lamotrigine/SCI
|
–
|
II
|
|
Svendsen et al., 2004
|
THC (Dronabinol)/MS
|
Third-line
|
+
|
II
|
B (Probably effective)*
|
+++
|
Not available / $$$$
|
|
Berman et al., 2004
|
CBD/THC/BPI
|
+
|
II
|
|
Rog et al., 2005
|
CBD/THC/MS
|
+
|
I
|
|
Langford et al., 2013
|
CBD/THC/MS
|
–
|
II
|
|
Schimrigk et al., 2017
|
THC (Dronabinol)/MS
|
–
|
II
|
|
Falah et al., 2011
|
Levetiracetam/MS
|
Non-favorable
|
–
|
II
|
B (Probably ineffective)
|
+++
|
Not available / $$$
|
|
Jungehulsing et al., 2012
|
Levetiracetam/CPSP
|
Non-favorable
|
–
|
II
|
|
Leijon et al., 1989
|
Carbamazepine/CPSP
|
Favorable in selected patients
|
–
|
II
|
C (Possibly ineffective)
|
+++
|
Available / $
|
|
Chiou-Tan et al., 1996
|
Mexiletine/SCI
|
Non-favorable
|
–
|
II
|
C (Possibly ineffective)
|
|
|
|
Drewes et al., 1994
|
Valproate/SCI
|
Non-favorable
|
–
|
II
|
C (Possibly ineffective)
|
|
|
EFNS: European Federation of Neurological Societies; SCI: Spinal Cord Injury; CPSP:
Central post-stroke Pain; MS: Multiple Sclerosis; BPI: Brachial Plexus Injury (with
avulsion); CBD: Canabidiol; THC: Delta-9-Tetrahydrocannabinol. *One should consider
this recommendation with caution, as formulations and doses are quite different between
studies. The initial level A recommendation was downgraded to level B because of this
heterogeneity. Drugs without research evidence:Venlafaxin and Opioids. $: low cost,
$$: medium cost, $$$: high cost, $$$$: very high cost; + low adverse effects; ++ low/medium
adverse effects; +++ high adverse effects.
Consensus recommendation
First-line therapy
Duloxetine
The use of duloxetine to treat CNP associated with multiple sclerosis was based on
two studies. In a low-quality, class I, positive study, Vollmer et al. used doses
of 60 mg (30 mg for one week, followed by 60 mg for five weeks) followed by a 12 week-open-label
extension phase (30-120 mg/day)[27]. Outcomes included daily changes in pain intensity, pain impact on daily activities,
quality of life, anxiety/depression, fatigue, and patients' global impression of improvement.
Results showed only a small decrease, although statistically significant, in pain
intensity at week six, accompanied by significant discontinuation of the intervention
due to adverse events.
Brown et al. used duloxetine to treat CNP in multiple sclerosis patients, in a high-quality,
positive, class II study[26]. Participants were treated with 30 mg/day for one week, followed by 60 mg/day for
five weeks, and 30 mg/day for one week, completing seven weeks of intervention. The
average daily pain was reduced by 39% in the active group compared to 10% in the placebo
group. Adverse events included nausea, dizziness, fatigue, constipation, and urinary
retention. Vranken et al. also used duloxetine (60 and 120mg/day) in patients with
CNP caused by spinal cord or stroke in a high-quality, class II, positive study[30]. They have found that duloxetine did not affect the mean pain score and pressure
pain thresholds after eight weeks, but alleviated dynamic and cold allodynia. Also,
they observed improvement for the bodily pain domain of the Short Form Health Survey
36 (SF-36), but no significant effect on the disability Index and the EQ-5D (instrument
for describing and valuing health, based on a descriptive system that defines health
in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort,
and Anxiety/Depression). Duloxetine was generally well tolerated, although dizziness,
decreased intellectual performance, and somnolence could be noted.
Duloxetine had a level C of recommendation (possibly effective) to treat CNP because
of two positive studies in the treatment of multilpe sclerosis (MS)-related CNP, and
one negative study in the treatment of SCI and poststroke CNP. However, the studies
used in this recommendation were very homogeneous (I2=0%), and effect size was moderate (0.73[0.39-1.06]) (Supplementary Figure S3), making
the quantitative synthesis very consistent. Hence, the consensus panel upgraded the
level of recommendation to B (probably effective) for the use of duloxetine in the
treatment of CNP. In accordance with this recommendation, duloxetine had a lower number
needed to treat (NNT) (6.4) than gabapentinoids in a recent guideline for neuropathic
pain in general[48].
Gabapentin
Gabapentin was used to treat CNP in spinal cord injury in a class II, low-quality,
positive study[29]. Paraplegic patients with pain were treated for four weeks with stable doses of
up to 3,600mg/day, after a four weeks period of titration. The treatment was efficient
in reducing >50% pain intensity, frequency, and almost all neuropathic pain descriptors
assessed (hot, sharp, unpleasantness, deep pain, and surface pain), also improving
quality of life, assessed by non-standard instruments (Lattinen test). Considering
the total number of adverse effects, which included weakness, edema, vertigo, sedation,
headache, and itching, it was significantly higher in patients treated with gabapentin
when compared to the placebo group.
Gabapentin reached a level C of recommendation (probably effective) in the treatment
of CNP. This was based on only one positive class II study, with a high effect size
(4.30[3.74-4.86], P<0.001) (Supplementary Figure S4), independent of its low quality.
Other guidelines present gabapentin as a first-line drug in the treatment of neuropathic
pain in general[48]. However, similar to pregabalin, gabapentin's NNT for the treatment of NP, in general,
is very high (7.2). As this drug may also be a reasonable option for CNP, future studies
should improve in quality, sample size, and diversity of CNP syndromes, in order to
investigate its specific efficacy.
Amitriptyline (and other tricyclics antidepressants)
Leijon et al. (1989) compared amitriptyline vs. carbamazepine and placebo interventions in periods of four weeks, in a low-quality,
class II, positive study[19]. Using final doses of 75 mg/day for amitriptyline, they found statistical significance
between groups for average pain intensity in central poststroke pain. Outcome measures
included the assessment of pain intensity and depression. Amitriptyline produced a
small decrease in pain intensity, an effect related to the plasma concentration of
the drug, with good tolerance to the final dose.
Amitriptyline was attributed a level C (possibly effective) in the treatment of CNP
because of one positive study in the treatment of post-stroke CNP. This study was
not included in quantitative synthesis, as although they reported mean and standard
deviations as statistical measures, their analysis of significance was based on non-parametric
tests, making means obsolete measures (Supplementary Figure S5). However, as this
drug is widely available in Brazil, at low cost and generally considered a first-line
medication in the treatment of neuropathic pain in general[48],[49], the consensus panel opted to maintain it as a first-line medication in the control
of CNP. The use of pregabalin, gabapentin, duloxetine and amitriptyline as first-line
drugs in the treatment of CNP is in accordance with other guidelines for NP in general[48],[49],[50]. However, it should be mentioned that CNP is more refractory than peripheral NP[51], making the development of new clinical trials investigating their effectiveness
in larger samples necessary, with different doses, and together with other pharmacological
and non-pharmacological approaches.
Second-line therapy
Pregabalin
The use of pregabalin for the treatment of CNP in spinal cord injury was based on
three positive[20],[21],[22] and one negative[31] studies. The first was a low-quality, positive study[20], which had more than 25 individuals per study arm, but was downgraded to class II
due to problems in blinding and attrition bias. They used 150, 300, or 600 mg/day
of the drug, twice a day, for 12 weeks. Results showed a dose-dependent effect, with
the medium dose of 460mg/day being more effective than the placebo in controlling
pain. Active intervention was associated with decreased The short-form McGill Pain
Questionnaire (SF-MPQ) scores, sleep problems, and anxiety. Patients' impression of
change was greater in the active group. Adverse events were seen in 75% of the participants
in the placebo group and 96% in the active group, being severe in 12% of the placebo
and in 19% of the active group. Somnolence and dizziness were the most frequent adverse
events, and euphoria was also reported, though only in the active group. The second
report was a high-quality, positive, class II study[22], which used 150 to 600mg of the drug, depending on the participants' responses to
the intervention during four weeks. The intervention was effective for pain relief,
measured through the Pain Disability Index, and the results were slightly positive
for quality of life through EQ-5D and in the bodily of the SF-36. Pregabalin, in a
flexible-dose regime, produced clinically significant reductions in pain intensity,
as well as improvements in health status. The most frequently reported adverse events
were central nervous system-related (dizziness, decreased intellectual performance,
and somnolence) and nausea. The incidence of these adverse events (mild or moderate
in intensity), however, did not differ significantly between treatment groups.
The third report was a high-quality, positive, class I study[21], which used a maximum of 600 mg/day, for 12 weeks. Results showed a significant
decrease in pain intensity, with almost 50% of the pregabalin group vs. 31.4% in the control group, achieving >30% of pain intensity relief. Positive differences
were also seen in sleep quality and depression, but not in anxiety. The fourth study
was the largest, with 219 participants allocated to the active or placebo groups.
This negative high-quality class I study used doses of 150 to 600 mg/day for 12 weeks
to treat CPSP. Results were negative for pain relief, but positive for improving sleep,
anxiety, and global impression of change. However, adverse events were more frequent
in the active group.
Based on the level of evidence alone, (presence of one class I and two class II positive,
and one class I negative studies), the drug received a recommendation level B (probably
beneficial). However, this recommendation was not supported by quantitative synthesis,
as although the overall effect size was positive (0.89[0.23-1.56], P<0.01) (Supplementary
Figure S6), the heterogeneity of the studies was high (I2=85%). Hence, based on the imprecision of the effect size[52], the level of recommendation for the use of pregabalin in the treatment of CNP was
downgraded to level C (possibly effective) by the consensus panel. This is in accordance
with recent guidelines for the treatment of NP in general[53], but points toward an urgent need to improve the quality of studies in the area.
The NNT of pregabalin in the treatment of peripheral and CNP was recently estimated
between 7.7 (6.5-9.4)and more than 9 including the most recent studies[48],[53]. These are high values, and would probably be higher in cases of CNP exclusively.
Weak opioids (in particular tramadol)
Tramadol, a weak mu-agonist which centrally acts in serotonin and noradrenaline reuptake
inhibition, is a second-line therapy for NP according to current guidelines[3],[54]. However, according to a recent systematic review, there is not enough data of adequate
quality to provide convincing evidence that tramadol is effective in relieving NP[54],[55]. Besides, along with all other opioid drugs, it has barely been studied specifically
in CNP patients. A single positive controlled study evaluated tramadol in CNP due
to SCI[55]; none were performed in CPSP and MS-CNP patients.
Lamotrigine
The use of lamotrigine in the control of CNP was investigated in three studies. In
the first study, Vestergaard et al. used 25, 50, 100, or 200mg lamotrigine to treat
poststroke CNP, a high-quality, class II, positive study[17]. Patients were treated for eight weeks, followed by a two-week washout period. The
active group showed a small decrease in median pain intensity with the 200mg dose
only. Effects were also seen in the physical pain item of the Global Pain Rating,
and in the acetone drop test, highlighting the potential use of this drug in the control
of cold allodynia present in CNP. The adverse effects of the drug were similar to
those of placebo. This study was not included in quantitative synthesis, as they reported
only the median as a central tendency measure.
In the second study, Finnerup et al. (2002), in a high-quality, class II, negative
RCT study using lamotrigine (maximum 400mg for 9 weeks) in spinal cord injury CNP,
have found no reduction in pain intensity, spasticity, sleep interference, and quality
of life in 42 patients [14]. However, they observed that, for patients with incomplete spinal cord injury, there
were significant reductions in at or below-level pain, tactile, pressure, and warm
threshold, compared with complete spinal cord lesion. Lamotrigine was generally well
tolerated, being necessary for only one patient to be withdrawn due to a rash. In
the third study, Breuer et al. used increasing doses of lamotrigine, up to 400mg/day
to treat multiple sclerosis-related CNP in a high-quality, class II, negative study[23]. Patients were treated for eight weeks, and the results showed no effects on none
of the outcome measures, directed to assess pain intensity and its impact on daily
life (mean pain - 0.80 [-1.55 - 3.15, P=0.5] (Supplementary Figure S7), neuropathic
pain characteristics or quality of life. In this study, adverse effects were more
frequent in the active group. As only the study of Breuer et al.[23] could be included in the quantitative synthesis, it was not possible to pool all
three studies in the meta-analysis. The consensus panel attributed a level B of recommendation
(possibly ineffective) to the use of lamotrigine to treat post-stroke, spinal cord
injury, and multiple sclerosis-related CNP. However, analysis of individual included
studies shows that it may help in the control of some characteristics of CNP, such
as painful spasms, paroxysms, and the presence of the Lhermitte's sign-related pain.
Venlafaxine
The use of venlafaxine in the treatment of CNP was not investigated in any of the
included studies. Analgesic effects are due to central noradrenergic effects, obtained
with higher doses of venlafaxine (150-225mg/day)[12],[48], being titrated from 37.5mg up and in some cases being used 300 mg/day. Advent or
worsening of high blood pressure must be monitored during treatment[56]. Hence, according to the specialists' opinions, it may be considered as a second-line
option or an alternative for duloxetine. CNP specific investigations are suggested.
Also, venlafaxine is a good option to treat commonly CNP-related anxiety and depressive
disorders.
Third-line therapy
Strong opioids (methadone, morphine, oxycodone, buprenorphine, fentanyl)
Most studies with opioids in NP evaluated post-herpetic neuralgia and other painful
peripheral neuropathies from different etiologies. As already mentioned above, no
controlled study has evaluated the use of strong opioids in the treatment of CNP.
A recent systematic review on the efficacy, tolerability, and safety of opioids in
non-cancer NP ponders that opioids may have a short-term substantial pain relief in
highly selected patients in some NP syndromes[57]. Despite the lack of good quality evidence, strong opioids — especially methadone
and morphine, affordable and accessible in the Brazilian health system — have been
used for CNP in patients refractory to treatment as an add-on therapy to first-line
medications in referred pain centers in Brazil. There is an obvious need for quality-controlled
studies to clarify the role of strong opioids in the treatment of CNP.
Cannabinoids
The use of specific cannabinoid combinations (delta-9-tetrahydrocannabinol (THC)/Cannabidiol
(CBD) for the treatment of CNP was based on three positive and two negative studies.
Rog et al. developed a high-quality class I study using CBD/THC to treat MS-related
CNP[37]. The drug was administered at doses of eight (21.6mg THC: 20mg CBD) to 48 (129.6mg
THC: 120mg CBD) sprays daily, for five weeks. There was a reduction of 41.5% in the
pain numeric rating scale (NRS), and 32.0% in the neuropathic pain scale (NPS) in
the active group, with a reduction of 22.1% in the NRS, and 17.6% in the NPS in the
sham group. There was also improvement in sleep in the active group, but no influence
on anxiety and depression scale or disability. The placebo group improved in neurophysiological
testing. Adverse events were identified in 88.2% of patients in the active group and
68.8% in the placebo group and were mainly with central characteristics in the active
group. Berman et al. used a cannabinoid-based approach (CBD/THC) to treat pain in
brachial plexus injury in a low-quality, class II, negative study[32]. The treatment consisted of THC 21.6mg, THC 21.6mg/CBD 20 mg or placebo, four to
eight times a day, for seven to 24 days. The results were significant, but not clinically
relevant in decreasing pain intensity, and improving sleep. Adverse events were small,
present only in one participant in each group. Svendsen et al. showed in a high-quality,
class II, positive study that dronabinol (cannabinoid), 2.5-5 mg, twice a day, for
three weeks was effective in the control of CNP in multiple sclerosis[33]. The intervention decreased more than 50% of pain intensity in almost half of the
participants in the active group (42-50%, depending on the order of crossover administration),
compared to 8 to 25% in the placebo group. Improvement in radiating pain, pressure
pain threshold, and mental health (SF-36) were seen in the active group. High adverse
events were observed in the first week, being mainly central and musculoskeletal complaints,
and were found in 96% of the participants in the active group, against 46% in the
control group. Langford et al. published a low-quality, class II, negative study using
THC/CBD oro-mucosal spray for 14 weeks in combination in CNP in 339 patients with
multiple sclerosis in an RCT and found differences in pain NRS and sleep quality without
difference between the respondents in phase I of the study[57]. Patients experienced no severe adverse events involving dizziness, fatigue, somnolence,
vertigo, and nausea. Schimrigk et al.[28] published a low-quality class II study using dronabinol to treat MS CNP, for 16
weeks. Dronabinol was not superior to placebo in decreasing pain intensity, and the
presence of adverse effects was higher in the active group.
The consensus panel recommended against the use of cannabinoids as monotherapy for
the treatment of CNP, based on two positive and two negative studies. Cannabis-based
drugs were considered as a third-line treatment, as an add-on drug or an alternative
for opioids in selected refractory patients. This recommendation is in accordance
with the quantitative synthesis, as the overall effect size was not significant (0.63
[-0.04 - 1.30], P=0.07) (Supplementary Figure S8), and with high heterogeneity (I2=74%). Also, among the four studies included, formulations and doses were quite heterogeneous,
and the quality of the studies was low in two of them. This recommendation is in line
with a recent review that failed to show beneficial effects in the treatment of neuropathic
pain in general[58]. Furthermore, at the present moment, cannabis-based drugs are not fully available
in the Brazilian public health system and are actually very high-cost medications,
which is likely to change in the years to come.
Combination of first-, second- and third-line drugs
A minority of CNP patients have full control of pain with a single drug. Monotherapy
often leads to a limited analgesic effect and dose-related side effects. In clinical
practice, the combination of drugs has been frequently used by specialists in order
to obtain a minimum satisfactory control of pain, of comorbidities commonly associated
with CNP such as depression, anxiety, and sleep disorders, and to help patients improve
functionality and quality of life. The combination of drugs may potentiate analgesic
effects due to synergistic properties and possibly allow the use of lower doses and
minimize the occurrence of adverse effects. However, studies that evaluated the combination
of drugs in chronic pain are scarce, mostly evaluated peripheral neuropathic pain,
and none was performed in CNP. A systematic review on combined pharmacotherapy in
NP pointed out that good quality studies have demonstrated superior efficacy of different
two-drug combinations, but it could not recommend the use of any specific combination
of drugs due to the limited trial sizes and duration[59]. Gabapentinoids have been commonly used in association with other drugs for the
treatment of NP patients. The absence of drug interactions and hepatic metabolism
favors its combination with other drugs such as the serotonin-norepinephrine reuptake
inhibitors (SNRI), for instance. However, safety concerns have been brought about
the combination of gabapentinoids and opioids. Gomes et al. described an increased
risk for opioid-related death due to respiratory depression in patients taking gabapentinoids[60].
Drugs classically used for neuropathic pain in general or CNP in particular, in Brazil,
and potentially able to benefit some patients
Carbamazepine
Leijon et al., in a low quality, class II, negative study, compared carbamazepine
vs. placebo intervention in periods of four weeks, using final doses of 800mg/day, and
found no statistical significance between groups for mean pain intensity in central
poststroke pain[19]. Outcome measures included the assessment of pain intensity and depression. Carbamazepine
was not effective and produced several adverse effects, generating high dropout rates
during the segment study. Carbamazepine has been classically used to treat trigeminal
neuralgia. In CNP, despite the paucity of studies, it can also be useful to treat
shock-like, paroxysmal NP, especially in SCI (e.g. Lhermitte's sign), even at low doses. In addition, carbamazepine is an affordable
and widely available drug in Brazil, even in SUS. Further studies are needed to establish
a role for carbamazepine in patients in specific subsets of CNP.
Summary of classification of selected studies
Based on these results and taking into account the positive or negative effects of
the drugs, specialists' opinions, balancing their adverse effects, cost, and availability
in SUS, [Table 1], [Figure 2] and Box 1 summarize the results of the consensus panel according to the use of drugs
to treat CNP in Brazil.
Figure 2 Central Neuropathic Pain guideline.
Special issues in prescribing drugs for CNP
Is pain in central nervous system (CNS) diseases always central neuropathic?
CNP happens after lesion or dysfunction of the CNS and is associated with signs of
central hyperexcitability, loss of sensation, spontaneous and/or abnormally evoked
pain, and other characteristics of maladaptive plasticity — plasticity leading to
decreased function in the CNS[61]. However, as signs and symptoms are very remarkable, little attention is put on
other possible sources of pain, including nociceptive and nociplastic pain. Other
sources of pain in patients with CNP include spasticity and spasms related pain[62],[63], musculoskeletal pain secondary to joint, muscle or myofascial dysfunction[63],[64], fatigue[65], migraine and tension-type headache[66], treatment pain[67],[68], peripheral neuropathy[69], and central sensitization or nociplastic pain[70]. Importantly, a recent study found that seven out of eight patients with post-stroke
CNP were relieved by a peripheral nerve block, suggesting that peripheral components
may have an important role in CNP[71]. Hence, a thorough evaluation of pain sources should contribute to the understanding
of the true role of central and peripheral mechanisms associated with CNP.
